Despite important advances in HIV-1 therapy over the past decade, most patients eventually exhaust their therapeutic options due to the emergence of multidrug-resistant virus and to the development of intolerable treatment related toxicities. The challenges are compounded by the increasing prevalence and transmission of multidrug-resistant isolates, and thus the development of new treatment strategies remains a high priority. HIV-1 entry proceeds via a cascade of interdependent events that provide promising targets for therapy. These events gpl20-CD4 attachment, gp 120-coreceptor interactions, and gp41 fusion. Inhibitors of each of these steps have shown promise in controlled clinical trials. PRO 542 (CD4-IgG2) is the most advanced inhibitor of HIV-1 attachment, and has demonstrated encouraging safety and antiviral profiles in single-dose studies. The fusion inhibitor T-20 recently became the first entry inhibitor to receive FDA approval for salvage therapy of HIV-1 infection, thus validating viral entry as a viable target for therapy. Single-dose PRO 542 has demonstrated particular promise in treating advanced HIV-1 disease, where the need for new treatment options is greatest; and the present project seeks to extend these findings to the multidose setting. The proposed Phase 2a clinical trial will examine the tolerability, pharmacokinetics and antiviral effects of escalating, multiple doses of PRO 542 in up to 24 treatment-experienced patients with advanced HIV-1 infection. The study design adheres to fundamental principles of antiretroviral therapy in seeking to maintain uniform serum trough concentrations of drug throughout the 3-week treatment period, and thus the study is intended to establish clear proof-of-concept for multidose PRO 542 in this important patient population. In addition, viral susceptibility to PRO 542 preand post-treatment will be measured and then correlated with clinical outcome. The viral and pharmacokinetic data will be used to assess the threshold steady-state drug concentrations required for effective therapy with this new agent. Success in the Phase I project would provide strong support and guidance for expanded clinical trials of multidose PRO 542 in the Phase II project. The expanded clinical studies would seek to establish the durability of therapy with this agent when used in combination with existing antiretroviral medications and thus would serve as a prelude to pivotal Phase 3 studies. The overall goal of this project is to expedite development of PRO 542 as the first of a potential new class of inhibitors of HIV-1 attachment.